A pharmacometric framework for norepinephrine transporter occupancy and dose equivalence across psychotropic medications.
Norepinephrine transporter (NET) inhibition is a relevant mechanism across psychotropic medications, although prescribing classifications are largely based on drug class rather than quantitative target engagement.
To facilitate cross-drug comparisons of noradrenergic activity, we developed a pharmacometric model to estimate NET occupancy for 26 psychotropic agents and their active metabolites.
NET occupancy was estimated using National Institute of Mental Health Psychoactive Drug Screening Program Ki data, protein-binding-corrected plasma concentrations, a standard receptor occupancy model, and logit-derived ED50 values, and was compared with published positron emission tomography (PET) estimates.
After protein-binding correction, desipramine, milnacipran, and maprotiline showed very high NET occupancy (⩾90%), nortriptyline, doxepin, and norquetiapine showed high occupancy (70%-90%), and hydroxybupropion and duloxetine showed moderate occupancy (50%-70%). Clomipramine, atomoxetine, and reboxetine demonstrated moderate-low occupancy (30%-50%), whereas venlafaxine showed low occupancy (~28%). Hydroxybupropion exhibited substantially greater NET engagement (~68%) than bupropion (~2%), and most Selective serotonin reuptake inhibitors showed minimal occupancy (<10%). Estimated ED50 values ranged from 6.6 mg (desipramine) to ⩾63 mg (duloxetine), and predicted occupancies correlated moderately with PET data (r = 0.76, p = 0.028, R² = 0.58).
These findings suggest that variability in NET engagement across psychotropic medications may not be fully captured by conventional class-based classifications. The proposed framework offers a mechanism-informed approach to comparative pharmacological analysis and introduces a conceptual noradrenergic activity index. This approach may be useful for hypothesis generation in future studies integrating pharmacokinetic-pharmacodynamic modeling with in vivo imaging and clinical outcomes.
To facilitate cross-drug comparisons of noradrenergic activity, we developed a pharmacometric model to estimate NET occupancy for 26 psychotropic agents and their active metabolites.
NET occupancy was estimated using National Institute of Mental Health Psychoactive Drug Screening Program Ki data, protein-binding-corrected plasma concentrations, a standard receptor occupancy model, and logit-derived ED50 values, and was compared with published positron emission tomography (PET) estimates.
After protein-binding correction, desipramine, milnacipran, and maprotiline showed very high NET occupancy (⩾90%), nortriptyline, doxepin, and norquetiapine showed high occupancy (70%-90%), and hydroxybupropion and duloxetine showed moderate occupancy (50%-70%). Clomipramine, atomoxetine, and reboxetine demonstrated moderate-low occupancy (30%-50%), whereas venlafaxine showed low occupancy (~28%). Hydroxybupropion exhibited substantially greater NET engagement (~68%) than bupropion (~2%), and most Selective serotonin reuptake inhibitors showed minimal occupancy (<10%). Estimated ED50 values ranged from 6.6 mg (desipramine) to ⩾63 mg (duloxetine), and predicted occupancies correlated moderately with PET data (r = 0.76, p = 0.028, R² = 0.58).
These findings suggest that variability in NET engagement across psychotropic medications may not be fully captured by conventional class-based classifications. The proposed framework offers a mechanism-informed approach to comparative pharmacological analysis and introduces a conceptual noradrenergic activity index. This approach may be useful for hypothesis generation in future studies integrating pharmacokinetic-pharmacodynamic modeling with in vivo imaging and clinical outcomes.